Exploration of 3-aryl pyrazole-tethered sulfamoyl carboxamides as carbonic anhydrase inhibitors

Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II. Compound 6g showed significant and selective inhibition toward hCA I and II, with Ki values of 0.0366 and 0.0310 & mu;M, respectively. Compound 5g exhibited the best inhibition toward mtCA 2, with a Ki value of 0.0617 & mu;M. Among the benzamides, compound 9b exhibited significant activity toward mtCA 2, with a Ki value of 0.0696 & mu;M. Selectivity of these compounds was further supported by docking studies. When tested for antitubercular activity, many compounds showed moderate to good inhibition against the Mtb H37Rv strain, with minimum inhibitory concentration (MIC) values in the range of 4-128 & mu;g/mL.Among pyrazole-based sulfamoyl acetamides 5-6, compound 6g showed significant and selective inhibition toward human carbonic anhydrases (hCA) I and II, and 5g exhibited the best inhibition toward mycobacterial tuberculosis carbonic anhydrase 2 (mtCA 2). Among the pyrazole-based sulfamoyl benzamides 9-10, compound 9b showed significant activity toward mtCA 2.image